US10406140B2 - 5-substituted benzimidazole and 5-substituted azabenzimidazole derivative both having AMPK activation effect - Google Patents

5-substituted benzimidazole and 5-substituted azabenzimidazole derivative both having AMPK activation effect Download PDF

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US10406140B2
US10406140B2 US16/099,574 US201716099574A US10406140B2 US 10406140 B2 US10406140 B2 US 10406140B2 US 201716099574 A US201716099574 A US 201716099574A US 10406140 B2 US10406140 B2 US 10406140B2
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substituted
unsubstituted
compound
heterocyclyl
heteroaryl
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US20190183866A1 (en
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Yuusuke Tamura
Toshihiro Wada
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Shionogi and Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • AMPK is a serine-threonine kinase, which is activated by AMP, and has three subunits, ⁇ , ⁇ and ⁇ . In each subunit, there exist multiple isoforms ( ⁇ 1, ⁇ 2, ⁇ 1, ⁇ 2, ⁇ 1, ⁇ 2 and ⁇ 3).
  • Patent Documents 1 to 18 disclose a variety of compounds having an AMPK activating effect. However, a benzimidazole or an azabenzimidazole derivative like the compound of the present invention is not disclosed in any of the documents.
  • Patent Documents 19 to 21 describe, as a compound having an AMPK activating effect, for example, compounds in which the 5-end of azabenzimidazole as shown below is substituted with a sulfoximine group, a carbamate group or the like, the 2-position is substituted with an isomannide group, and the 6-position is substituted with chloro.
  • Patent Document 22 describes, for example, the compounds shown below as a compound having an AMPK activating effect.
  • Patent Document 23 describes, for example, the compounds shown below as a compound having an AMPK activating effect.
  • An object of the present invention is to provide an excellent AMPK activator.
  • the present invention relates to the following.
  • R 1 is hydrogen, or substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
  • T is —CR 5 ⁇ or —N ⁇
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl
  • Y is substituted or unsubstituted or unsub
  • n is an integer 1 or 2;
  • R S and R S′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R S and R S′ bound to the same sulfur atom may form a substituted or unsubstituted ring together with the sulfur atom;
  • R S′′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2f is substituted or unsubstituted alkylene;
  • R N is each independently hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubsti
  • R 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R 2 is cycloalkyl or heterocyclyl substituted with at least one group selected from halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and substituted or unsubstituted amino,
  • R 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl substituted with at least one halogen
  • R 2 is cycloalkyl or heterocyclyl substituted with at least one halogen, and further optionally substituted with —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 6 is each independently halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino;
  • a is an integer from 1 to 3;
  • R 7 is each independently hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl;
  • b is an integer from 0 to 8;
  • c is an integer from 0 to 6;
  • d is an integer from 0 to 8;
  • e is an integer from 0 to 10;
  • f is an integer from 0 to 6.
  • R 6 and a are as defined in the above (8).
  • a method for preventing or treating diabetes comprising administering the compound according to any one of the above (1) to (24), or its pharmaceutically acceptable salt.
  • a pharmaceutical composition for oral administration comprising a compound represented by formula (I), or its pharmaceutically acceptable salt,
  • composition according to the above (30) which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction or tincture.
  • composition according to the above (33) or (34) which is injection, infusion, ophthalmic drop, nose drop, ear drop, aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder or suppository.
  • a pharmaceutical composition for a pediatric or geriatric patient comprising a compound represented by formula (I), or its pharmaceutically acceptable salt.
  • a pharmaceutical composition consisting of a combination of a compound represented by formula (I) or its pharmaceutically acceptable salt, and an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • a pharmaceutical composition comprising a compound represented by formula (I) or its pharmaceutically acceptable salt, for a combination therapy with an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • a compound represented by formula (I) or its pharmaceutically acceptable salt for a combination therapy with an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • R 1 is hydrogen, or substituted or unsubstituted alkyl
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl;
  • T is —CR 5 ⁇ or —N ⁇
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl
  • Y is substituted or unsubstituted or unsub
  • n is an integer 1 or 2;
  • R S and R S′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R S and R S′ bound to the same sulfur atom may form a substituted or unsubstituted ring together with the sulfur atom;
  • R S′′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 2f is substituted or unsubstituted alkylene;
  • R N is each independently hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubsti
  • R 3 is fluoro, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • R 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl substituted with at least one group selected from halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and substituted or unsubstituted amino,
  • R 2 is cycloalkyl or heterocyclyl substituted with at least one group selected from halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and substituted or unsubstituted amino,
  • R 2 is cycloalkyl or heterocyclyl substituted with at least one halogen, and further optionally substituted with —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 6 is each independently halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino;
  • a is an integer from 1 to 3;
  • R 7 is each independently hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl;
  • b is an integer from 0 to 8;
  • c is an integer from 0 to 6;
  • d is an integer from 0 to 8;
  • e is an integer from 0 to 10;
  • f is an integer from 0 to 6.
  • R 6 and a are as defined in the above (8A).
  • R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl; and R 3 is fluoro, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • a pharmaceutical composition comprising the compound according to any one of the above (1A) to (23A), or its pharmaceutically acceptable salt.
  • composition according to the above (24A), which has an activating effect on adenosine monophosphate-activated protein kinase which has an activating effect on adenosine monophosphate-activated protein kinase.
  • a method for preventing or treating diabetes comprising administering the compound according to any one of the above (1A) to (23A), or its pharmaceutically acceptable salt.
  • a pharmaceutical composition for oral administration comprising a compound represented by formula (I), or its pharmaceutically acceptable salt,
  • composition according to the above (29A) which is a tablet, powder, granule, capsule, pill, film, suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction or tincture.
  • composition according to the above (30A) which is a sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup, soft capsule, micro capsule or sustained-release capsule.
  • a pharmaceutical composition for parenteral administration comprising a compound represented by formula (I), or its pharmaceutically acceptable salt.
  • composition according to the above (32A) for dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear or vaginal administration.
  • composition according to the above (32A) or (33A) which is injection, infusion, ophthalmic drop, nose drop, ear drop, aerosol, inhalation, lotion, impregnation, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder or suppository.
  • a pharmaceutical composition consisting of a combination of a compound represented by formula (I) or its pharmaceutically acceptable salt, and an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • a pharmaceutical composition comprising a compound represented by formula (I) or its pharmaceutically acceptable salt, for a combination therapy with an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • a compound represented by formula (I) or its pharmaceutically acceptable salt for a combination therapy with an insulin secretagogue, a fast-acting insulin secretagogue, a glucose uptake inhibitor, an insulin resistance improving drug, a thiazolidine derivative, an insulin formulation, a peptidyl peptidase IV inhibitor, a GLP-1 receptor agonist, a sodium-dependent glucose transporter 1 inhibitor, or a sodium-dependent glucose transporter 2 inhibitor.
  • the compound of the present invention has an AMPK activating effect, and thus a pharmaceutical composition comprising a compound of the pre sent invention is very useful as a medicinal product, particularly, a medicine for treating and/or preventing type II diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and/or hypertension. Further, the compound of the present invention is a compound which has usefulness as a medicine.
  • the usefulness as a medicine herein comprises good metabolic stability, slight induction of a drug-metabolizing enzyme, slight inhibition of drug-metabolizing enzymes which metabolize other drugs, high oral absorption, low clearance, a sufficiently long half-life period to express the efficacy of a medicine, a high enzyme activity, a high maximal activation rate, a low protein binding rate, high penetration into target tissue, high solubility, high safety, an insulin resistance improving effect based on an energy consumption increase, the effect of decreasing hemoglobin A 1C (HbA1c), the effect of improving fatty hepatic or the like.
  • HbA1c hemoglobin A 1C
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Alkyl means a C1 to C10 straight or branched alkyl group, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
  • Preferable examples include C1 to C6 or C1 to C4 alkyl, and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and isohexyl.
  • Alkenyl means C2 to C8 straight or branched alkenyl having one or more double bond(s) in the above “alkyl”, and examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl and the like.
  • Alkynyl means C2 to C8 straight or branched alkynyl having one or more triple bond(s) in the above “alkyl”, and examples thereof include ethynyl, propynyl, butynyl and the like. Furthermore, an “alkynyl” may have a double bond.
  • Cycloalkyl means a C3 to C15 cyclic saturated hydrocarbon group, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bridged cyclic hydrocarbon group, spiro hydrocarbon group and the like. Preferable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or bridged cyclic hydrocarbon group.
  • a “bridged cyclic hydrocarbon group” includes a group which is derived by removing one hydrogen from a C5 to C8 aliphatic cycle which consists of two or more rings that share two or more atoms. Specific examples thereof include bicyclo[2.1.0]pentyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[2.2.1.0]heptyl and the like.
  • a “spiro hydrocarbon group” includes a group which is derived by removing one hydrogen from a cycle which consists of two hydrocarbon rings that share one carbon atom. Specific examples thereof include spiro[3.4]octyl and the like.
  • “Cycloalkenyl” means C3 to C10 cyclic unsaturated aliphatic hydrocarbon group, and examples thereof include cyclopropenyl (e.g., 1-cyclopropenyl), cyclobutenyl (e.g., 1-cyclobutenyl), cyclopentenyl (e.g., 1-cyclopenten-1-yl, 2-cyclopenten-1-yl and 3-cyclopenten-1-yl), cyclohexenyl (e.g., 1-cyclohexen-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl), cycloheptenyl (e.g., 1-cycloheptenyl), cyclooctenyl (e.g., 1-cyclooctenyl) and the like.
  • cyclopropenyl e.g., 1-cyclopropenyl
  • cyclobutenyl e.g., 1-cyclobuteny
  • Cycloalkenyls also include bridged cyclic hydrocarbon group and spiro hydrocarbon group which both have an unsaturated bond in the ring. Cycloalkenyls also include cyclic groups in which cycloalkene or a benzene ring is condensed with the cycloalkyl. For examples, cycloalkenyls also include the groups shown below.
  • Aryl means a monocyclic aromatic hydrocarbon group (e.g., phenyl) and a polycyclic aromatic hydrocarbon group (e.g., 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, 9-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl, 9-phenanthryl, etc.).
  • Preferable examples include phenyl or naphthyl (1-naphthyl or 2-naphthyl).
  • Heteroaryl means a monocyclic aromatic heterocyclic group and a fused aromatic heterocyclic group.
  • a “monocyclic aromatic heterocyclic group” means a group which is derived from a 5 to 8-membered aromatic ring which has one or more same or different heteroatoms optionally selected from oxygen, sulfur and nitrogen atoms in the ring, which group may have a bond at any substitutable position.
  • a “fused aromatic heterocyclic group” means a group in which a 5 to 8-membered aromatic ring which has one or more same or different heteroatoms optionally selected from oxygen, sulfur and nitrogen atoms in the ring is fused with one to four 5 to 8-membered aromatic carbocyclic rings or another 5 to 8-membered aromatic hetero ring, which group may have a bond at any substitutable position.
  • heteroaryl examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), e
  • Heterocyclyl means a non-aromatic heterocyclic group, which may have a bond at any substitutable position of a ring which has at least one or more nitrogen, oxygen or sulfur atoms in the ring, or a ring in which such ring is fused with a cycloalkane (preferably 5 to 6-membered), a benzene ring and/or a ring which has at least one or more nitrogen, oxygen or sulfur atoms in the ring.
  • a “non-aromatic heterocyclic group” can be saturated or unsaturated as long as it is non-aromatic. Preferable is a 5- to 10-membered ring.
  • Examples thereof include 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolinyl, 4-imidazolinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 1-pyrazolidinyl, 3-pyrazolidinyl, 4-pyrazolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-piperazinyl, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydr
  • heterocyclyl examples also include a bridged group or a spiro ring forming group shown below.
  • “Acyl” means formyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted cycloalkenylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted heterocyclylcarbonyl.
  • alkyl part of “alkylcarbonyl”, the “alkenyl” part of “alkenylcarbonyl”, the “cycloalkyl” part of “cycloalkylcarbonyl”, the “cycloalkenyl” part of “cycloalkenylcarbonyl”, the “aryl” part of “arylcarbonyl”, the “heteroaryl” part of “heteroarylcarbonyl” and the “heterocyclyl” part of “heterocyclylcarbonyl” mean the above “alkyl”, the above “alkenyl”, the above “cycloalkyl”, the above “cycloalkenyl”, the above “aryl”, the above “heteroaryl” and the above “heterocyclyl”, respectively.
  • alkyl parts of “alkylcarbonyl”, “alkyloxycarbonyl”, “alkylcarbamoyl”, “alkylsulfonyl”, “alkyloxy” and “alkylthio” mean the above “alkyl”.
  • arylcarbonyl aryloxycarbonyl
  • arylsulfonyl aryloxy
  • arylthio aryl
  • heteroaryl parts of “heteroarylcarbonyl”, “heteroaryloxy”, “heteroarylthio” and “heteroarylsulfonyl” mean the above “heteroaryl”.
  • cycloalkenyl parts of “cycloalkenyloxy”, “cycloalkenylthio” and “cycloalkenylsulfonyl” mean the above “cycloalkenyl”.
  • heterocyclyl parts of “heterocyclylcarbonyl”, “heterocyclyloxy”, “heterocyclylthio” and “heterocyclylsulfonyl” mean the above-described “heterocyclyl”.
  • substituted or unsubstituted alkyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl heterocyclyl, alkylcarbonylamino. e.g., methyl, ethyl, isopropyl, tert-butyl, CF 3 );
  • substituted or unsubstituted alkenyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., vinyl);
  • substituted or unsubstituted alkynyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., ethynyl);
  • substituted or unsubstituted aryl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., phenyl, naphthyl);
  • substituted or unsubstituted cycloalkenyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., cyclopropenyl);
  • substituted or unsubstituted heteroaryl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., morpholinyl, piperidyl, pyrrolidinyl);
  • substituted or unsubstituted alkyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., methoxy, ethoxy);
  • substituted or unsubstituted alkenyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., vinyloxy, allyloxy);
  • substituted or unsubstituted aryloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., phenyloxy);
  • substituted or unsubstituted cycloalkyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkenyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted arylalkyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., benzyl);
  • substituted or unsubstituted amino e.g., amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino), arylamino, cycloalkylamino, cycloalkenylamino, heteroarylamino, heterocyclylamino, acylamino (e.g., acetylamino, benzoylamino), arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, alkyloxycarbonylamino, carbamoylamino, alkylsulfonylamino, arylsulfonylamino, cycloalkylsulfonylamino, cycloalkenylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino); substituted or unsubstitute
  • alkylcarbonyl e.g., alkylcarbonyl, arylcarbonyl, cycloalkylcarbonyl, cycloalkenylcarbonyl, heteroarylcarbonyl, heterocyclylcarbonyl, formyl, acetyl
  • substituted or unsubstituted alkylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl.
  • substituted or unsubstituted aryloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl); substituted or unsubstituted cycloalkyloxycarbonyl (when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl); substituted or unsubstituted cycloalkenyloxycarbonyl (when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl); substituted or unsubstituted cycloalkenyloxycarbonyl (when substituted, substitu
  • substituted or unsubstituted alkenyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., vinyl);
  • substituted or unsubstituted aryl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., phenyl, naphthyl);
  • substituted or unsubstituted cycloalkyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., cyclopropyl, cyclobutyl);
  • substituted or unsubstituted heteroaryl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted alkyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., methoxy, ethoxy);
  • substituted or unsubstituted aryloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., phenyloxy);
  • substituted or unsubstituted cycloalkyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkenyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heteroaryloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclyloxy when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted acyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted alkyloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl);
  • substituted or unsubstituted aryloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkyloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkenyloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heteroaryloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclyloxycarbonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted sulfamoyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted alkylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl. e.g., methanesulfonyl, ethanesulfonyl);
  • substituted or unsubstituted arylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heteroarylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkenylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclylsulfonyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted carbamoyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted alkylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted cycloalkenylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted arylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heteroarylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • substituted or unsubstituted heterocyclylsulfinyl when substituted, substituents include halogen, hydroxy, carboxy, nitro, cyano, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl);
  • alkyl parts of “arylalkyl”, “alkylamino”, “arylalkylamino”, “alkyloxycarbonylamino”, “alkylsulfonylamino”, “heteroarylalkylcarbamoyl”, “alkylthio” and “alkylsulfinyl” mean the above-described “alkyl”.
  • alkenyl part of “alkenyloxy” means the above-described “alkenyl”.
  • arylalkyl arylamino
  • arylalkylamino arylalkylamino
  • arylsulfonylamino arylsulfinyl
  • heteroaryl parts of “heteroarylamino”, “heteroarylsulfonylamino”, “heteroarylalkylcarbamoyl”, “heteroaryloxycarbonyl” and “heteroarylsulfinyl” mean the above-described “heteroaryl”.
  • cycloalkyl parts of “cycloalkylamino”, “cycloalkylsulfonylamino”, “cycloalkyloxycarbonyl” and “cycloalkylsulfinyl” mean the above-described “cycloalkyl”.
  • cycloalkenyl parts of “cycloalkenylamino”, “cycloalkenylsulfonylamino”, “cycloalkenyloxycarbonyl” and “cycloalkenylsulfinyl” mean the above-described “cycloalkenyl”.
  • heterocyclyl parts of “heterocyclylamino”, “heterocyclylsulfonylamino”, “heterocyclyloxycarbonyl” and “heterocyclylsulfinyl” mean the above-described “heterocyclyl”.
  • R 1 is hydrogen, or substituted or unsubstituted alkyl. Preferably, R 1 is hydrogen.
  • R 2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R 2 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl substituted with at least one group selected from halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and substituted or unsubstituted amino, and further optionally substituted with hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl substituted with at least one halogen,
  • substituted or unsubstituted heteroaryl substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 2 is cycloalkyl or heterocyclyl substituted with at least one halogen
  • substituted or unsubstituted heteroaryl substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 2 examples include the following rings.
  • R 6 , R 7 , a, b, c, d, e and f are as defined above.
  • R 2 examples of further preferred embodiments of R 2 include the following rings.
  • R 6 and a are as defined above.
  • R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl
  • R 3 is fluoro, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy are also preferred.
  • R 3 is fluoro, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy are also preferred.
  • R 6 is each independently halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, or substituted or unsubstituted amino.
  • R 6 is halogen
  • a is an integer from 1 to 3. Preferably, a is 1 or 2.
  • R 7 is each independently hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkylsulfonyl, or substituted or unsubstituted acyl.
  • R 7 is each independently hydroxy, carboxy, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • b is an integer from 0 to 8.
  • b is an integer of 0 to 3.
  • b is 1 or 2.
  • b is 1.
  • c is an integer from 0 to 6.
  • c is an integer of 0 to 3.
  • c is 1 or 2.
  • c is 1.
  • d is an integer from 0 to 8.
  • d is an integer of 0 to 3.
  • d is an integer of 0 to 2.
  • e is an integer from 0 to 10.
  • e is an integer of 0 to 3.
  • e is 1.
  • f is an integer from 0 to 6.
  • f is an integer of 0 to 3.
  • f is 1.
  • T is —CR 5 ⁇ or —N ⁇ .
  • T is —N ⁇ .
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl.
  • X is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • Y is substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl.
  • Z is R S R S′ (O ⁇ )S ⁇ N—, R S R S′ (O ⁇ )S ⁇ N—R 2f —, R S R S′ (O ⁇ )S ⁇ N—C( ⁇ O)—, (R N )N ⁇ S( ⁇ O)(R S )—, (R N )N ⁇ S( ⁇ O)(R S )—R 2f —, R S R S′ (R N′ —N ⁇ )S ⁇ N—, ((R N )N ⁇ ) 2 S(R S′′ )—, (R N R N′ )N—C( ⁇ O)—O—, R O O—C( ⁇ O)—N(R N )—, R O O—C( ⁇ O)—O—, R S (R N R N′ N)(O ⁇ )S ⁇ N—, R S (R N R N′ N)(O ⁇ )S ⁇ N—, R S (R N R N′ N)(O ⁇ )S ⁇ N—R 2f —, (R N′′ )
  • Z is R S R S′ (O ⁇ )S ⁇ N—, (R N )N ⁇ S( ⁇ O)(R S )—, ((R N )N ⁇ ) 2 S(R S′′ )—, R O O—C( ⁇ O)—N(R N )—, or R S (R N R N′ N)(O ⁇ )S ⁇ N—.
  • n is an integer 1 or 2.
  • R S and R S′ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R S and R S′ which are bound to the same sulfur atom may form a substituted or unsubstituted ring together with the sulfur atom.
  • R S and R S′ are each independently substituted or unsubstituted alkyl.
  • the ring which is formed by R S and R S′ which are bound to the same sulfur atom, together with the sulfur atom, means a 3 to 15-membered saturated or unsaturated hetero ring that may contain one to four oxygen, nitrogen and/or sulfur atom(s) in the ring, other than the sulfur atom.
  • a non aromatic ring and such non aromatic ring may be further cross-linked by a C1 to C4 alkyl chain, and may be fused with cycloalkane (preferably 5 to 6-membered) and a benzene ring. Examples thereof include as follows.
  • R S′′ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R S′′ is substituted or unsubstituted alkyl.
  • R 2f is substituted or unsubstituted alkylene.
  • R N is each independently hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylcarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylcarbonyl, or substituted or unsubstituted carbamoyl; and
  • R N is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbamoyl.
  • R N is each independently hydrogen, or substituted or unsubstituted alkyl.
  • Examples of the ring formed by two (R N )N ⁇ which are bound to the same sulfur atom together with the sulfur atom, when Z is ((R N )N ⁇ ) 2 S(R S′′ )—, include as follows.
  • R N′ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylcarbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heterocyclylcarbonyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylcarbonyl or substituted or unsubstituted carbamoyl; R N and R N′ which are bound to the same nitrogen atom may form a substituted or unsubstituted ring together with the nitrogen atom.
  • R N′ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R N′ is hydrogen, or substituted or unsubstituted alkyl.
  • R N′′ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkylcarbamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted cycloalkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted acyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted al
  • R N′′ is hydrogen, or substituted or unsubstituted alkyl.
  • R O is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R O is substituted or unsubstituted alkyl.
  • R P1 and R P2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
  • R P1 is substituted or unsubstituted alkyl.
  • R P2 is substituted or unsubstituted alkyl.
  • R 3 , R 4 and R 5 are each independently hydrogen, halogen, hydroxy, cyano, nitro, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted heterocyclyloxy, substituted or unsubstituted alkylthio, substitute
  • R 3 is preferably halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • R 3 is fluoro, chloro, cyano or substituted or unsubstituted alkyl, and the substituent of the substituted alkyl is halogen.
  • R 3 is fluoro or chloro.
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl or heterocyclyl substituted with at least one group selected from halogen, —PO(OH) 2 , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkylthio, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl and substituted or unsubstituted amino, T is —N ⁇ , X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl, Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl
  • T is —N ⁇
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
  • R 4 is hydrogen
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl,
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
  • Z is R S R S′ (O ⁇ )S ⁇ N—, (R N )N ⁇ S( ⁇ O)(R S )—, ((R N )N ⁇ ) 2 S(R S′′ )—, R O O—C( ⁇ O)—N(R N )—, or R S (R N R N′ N)(O ⁇ )S ⁇ N—,
  • R 3 is halogen, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, and
  • R 4 is hydrogen
  • R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl
  • T is —N ⁇
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
  • R 3 is fluoro, cyano, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy, and
  • R 4 is hydrogen
  • R 2 is substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl
  • T is —N ⁇
  • X is a single bond, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclyl,
  • Y is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl,
  • Z is R S R S′ (O ⁇ )S ⁇ N—, (R N )N ⁇ S( ⁇ O)(R S )—, ((R N )N ⁇ ) 2 S(R S′′ )—, R O O—C( ⁇ O)—N(R N )—, or R S (R N R N′ N)(O ⁇ )S ⁇ N—,
  • R 3 is fluoro
  • R 4 is hydrogen
  • One or more hydrogen, carbon or other atoms of the compounds of formula (I) of the present invention can be replaced by an isotope of the hydrogen, carbon or other atoms.
  • the compounds of formula (I) include all radiolabeled forms of compounds of formula (I).
  • radiolabeled forms of compounds of formula (I) Such “radioactive labeling,” “radiolabeled form” and the like of the compounds of formula (I) are encompassed by the present invention and useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies and in binding assays.
  • isotopes that can be incorporated into a compound of formula (I) of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • Radiolabeled compounds of the present invention can be prepared by methods well-known in the art.
  • tritium-labeled compounds of formula (I) can be prepared by introducing tritium into a particular compound of formula (I), for example, by catalytic dehalogenation with tritium.
  • This method may include reacting a suitably halogen-substituted precursor of a compound of formula (I) with tritium gas in the presence of a suitable catalyst such as Pd/C, in the presence or absence of a base.
  • a suitable catalyst such as Pd/C
  • Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • 14 C-labeled compounds can be prepared by employing starting materials having a 14 C carbon.
  • examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and strontium salts; beryllium salts, magnesium salts; transition metal salts such as zinc salts; ammonium salts; aliphatic amine salts such as trimethylamine salts, triethylamine salts, dicyclohexylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, procaine salts, meglumine salts, diethanolamine salts and ethylenediamine salts; aralkylamine salts such as N,N-dibenzylethylenediamine and benethamine salts; heterocyclic aromatic amine salts such as pyridine salts, picoline salts, quinoline salts, and isoquinoline salts; quaternary ammonium salts such as tetramethylammonium salts, tetraethylammonium salts, benz
  • a compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt may form a solvate (e.g., hydrate, etc.), cocrystal and/or a crystal polymorph, and the present invention also contains such various types of solvates, cocrystal and crystal polymorphs.
  • a solvate any number of solvent molecules (e.g., water molecule, etc.) may be coordinated with a compound represented by formula (I).
  • a compound represented by formula (I) or its pharmaceutically acceptable salt may absorb water, and a case where adsorbed water is attached thereto or a case where hydrate is formed may arise.
  • crystal polymorph thereof can be formed.
  • the “cocrystal” means that a compound represented by formula (I) or its salt and a counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecule.
  • a compound represented by formula (I) of the present invention or its pharmaceutically acceptable salt may form a prodrug, and the present invention also contains such various types of prodrugs.
  • the prodrugs are a derivative of the compound of the present invention, which has a chemically or metabolically decomposable group, and a compound which is changed into the compound of the present invention, which is pharmaceutically active, by solvolysis or in vivo under physiological conditions.
  • the prodrugs contain a compound which is converted into a compound represented by formula (I) by enzymatic oxidation, reduction, hydrolysis and the like in living organisms under physiological conditions; a compound which is converted into a compound represented by formula (I) by hydrolysis by e.g., gastric acid; and the like.
  • a method for selecting and a method for producing a proper prodrug derivative are described in e.g., Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs can have activity in themselves.
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives are exemplified, which derivatives are produced, for example, by a reaction of a compound having a hydroxyl group and a proper acyl halide, a proper acid anhydride, a proper sulfonyl chloride, a proper sulfonyl anhydride and a mixed anhydride, or a reaction using a condensing agent.
  • Examples thereof include CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH(NH 2 )COO—, CH 2 N(CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p-CH 3 O-PhSO 3 —, PhSO 3 — and p-CH 3 PhSO 3 —.
  • activating means that the compound of the present invention activates the function of AMPK.
  • pharmaceutically acceptable means preventively or therapeutically harmless.
  • a compound represented by formula (I-1) can be synthesized as follows.
  • a known compound can be used, or a compound which is derived from a known compound by a conventional method may be used.
  • “Hal” means a halogen
  • Pro means a protecting group. Pro includes a benzyl group, a p-methoxybenzyl group, an acetyl group, a benzoyl group, SEM (trimethylsilylethoxymethyl), THP (tetrahydropyran), TBS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl) and the like.
  • the first step is a step in which a compound represented by formula (A-2) is produced by reacting a compound represented by formula (A-1) and a compound represented by formula: H—O—R 2 .
  • examples include N,N-dimethylformamide, dimethyl sulfoxide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), saturated hydrocarbons (e.g., cyclohexane, hexane, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), ketones (e.g., acetone, methyl ethyl ketone, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, t-butan
  • Preferred examples include N,N-dimethylformamide, dimethyl sulfoxide, ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (e.g., acetonitrile, etc.) and the like.
  • ethers e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles e.g., acetonitrile, etc.
  • examples include metal hydrides (e.g., sodium hydride, etc.), metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, etc.), metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.), metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), sodium hydrogencarbonate, metal sodium, metal amides, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.), pyridine, alkyllithiums (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides e.g., sodium hydride, etc.
  • metal hydroxides e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydrox
  • Preferred examples include metal hydrides (e.g., sodium hydride, etc.), metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.), metal amides, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.), pyridine, alkyllithiums (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal hydrides e.g., sodium hydride, etc.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • metal amides e.g., organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.), pyridine, alkyllithiums (n-BuLi, sec-BuLi, tert-Bu
  • metal hydrides e.g., sodium hydride, etc.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • the reaction can be carried out at 0 to 100° C. for 0.5 to 12 hours.
  • the reaction can be carried out using conditions for a reaction which is known as the Ullmann reaction.
  • reaction solvent As a reaction solvent, the above solvents can be used. Preferred examples include N,N-dimethylformamide, dimethyl sulfoxide, ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), nitriles (e.g., acetonitrile, etc.) and the like.
  • ethers e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.
  • nitriles e.g., acetonitrile, etc.
  • the above bases can be used.
  • Preferred examples include metal hydrides (e.g., sodium hydride, etc.), metal carbonates (e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.), metal amides, organic amines (e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.), pyridine, alkyllithiums (n-BuLi, sec-BuLi, tert-BuLi) and the like.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • copper iodide As a catalyst, copper iodide can be used.
  • the reaction can be carried out at room temperature to 100° C. for 0.5 to 12 hours.
  • the second step is a step in which a compound represented by formula (A-4) is produced by reacting a compound represented by formula (A-2) and a compound represented by formula (A-3) in the presence of a palladium catalyst.
  • a compound represented by formula (A-3) boronic acid ester may be used.
  • solvents described for the first step can be used.
  • N,N-dimethylformamide, aromatic hydrocarbons (e.g., toluene, benzene, xylene, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.) or alcohols (e.g., methanol, ethanol, t-butanol, etc.) can be used.
  • bases described for the first step can be used.
  • metal carbonates e.g., sodium carbonate, calcium carbonate, cesium carbonate, etc.
  • organic amines e.g., triethylamine, diisopropylethylamine, DBU, 2,6-lutidine, etc.
  • the reaction may be carried out in the presence of a palladium catalyst (e.g., Pd(PPh 3 ) 4 , PdCl 2 , Pd(OAc) 2 , Pd(dba) 2 , etc.) and a phosphine ligand (e.g., PPh 3 , BINAP, etc.) at a temperature, at which a solvent to be used is refluxed, for 0.5 to 12 hours.
  • a palladium catalyst e.g., Pd(PPh 3 ) 4 , PdCl 2 , Pd(OAc) 2 , Pd(dba) 2 , etc.
  • a phosphine ligand e.g., PPh 3 , BINAP, etc.
  • the reaction can be carried out at 80 to 200° C. for 5 minutes to one hour.
  • the third step is a step in which a compound represented by formula (I-1) is produced by deprotection of a compound represented by formula (A-4).
  • solvents described for the first step can be used.
  • Preferred examples include N,N-dimethylformamide, halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.), ethers (e.g., tetrahydrofuran, diethyl ether, dioxane, 1,2-dimethoxyethane, etc.), esters (e.g., methyl acetate, ethyl acetate, etc.), nitriles (e.g., acetonitrile, etc.), alcohols (e.g., methanol, ethanol, t-butanol, etc.) and the like.
  • halogenated hydrocarbons e.g., dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • ethers e.g., tetrahydrofuran, diethyl ether, dioxane,
  • the reaction can be carried out in the presence of hydrochloric acid, TFA (trifluoroacetic acid), TBAF (tetrabutylammoniumfluoride) or the like at 0 to 100° C. for 0.5 to 24 hours.
  • hydrochloric acid TFA (trifluoroacetic acid)
  • TBAF tetrabutylammoniumfluoride
  • a compound, wherein R 1 is substituted or unsubstituted alkyl can be synthesized, for example, from a compound represented by formula (I-1) by an alkylation reaction using sodium hydride and an alkyl halide.
  • a compound of the present invention has an excellent AMPK activating effect. Therefore, the compound can be used for the treatment or prevention of diseases associated with AMPK, particularly disease such as type I diabetes, type II diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and/or hypertension. Particularly, the compound is useful in the treatment or prevention of type II diabetes, hyperglycemia, metabolic syndrome or obesity.
  • a pharmaceutical composition of the present invention can be administered orally or parenterally.
  • Methods for parenteral administration include dermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, transnasal, ophthalmic, inner ear or vaginal administration and the like.
  • any forms which are usually used, such as oral solid formulations (e.g., tablets, powders, granules, capsules, pills, films or the like), oral liquid formulations (e.g., suspension, emulsion, elixir, syrup, lemonade, spirit, aromatic water, extract, decoction, tincture or the like) and the like may be prepared according to the usual method and administered.
  • the tablets can be sugar-coated tablets, film-coated tablets, enteric-coating tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets. Powders and granules can be dry syrups.
  • Capsules can be soft capsules, micro capsules or sustained-release capsules.
  • any forms which are usually used, such as injections, drips, external preparations (e.g., ophthalmic drops, nasal drops, ear drops, aerosols, inhalations, lotion, infusion, liniment, mouthwash, enema, ointment, plaster, jelly, cream, patch, cataplasm, external powder, suppository or the like) and the like can be preferably administered.
  • Injections can be emulsions whose type is O/W, W/O, O/W/O, W/O/W or the like.
  • the pharmaceutical composition may be manufactured by mixing an effective amount of the compound of the present invention with various pharmaceutical additives suitable for the formulation, such as excipients, binders, disintegrants, lubricants and the like.
  • the pharmaceutical composition can be for pediatric patients, geriatric patients, serious cases or operations by appropriately changing the effective amount of the compound of the present invention, formulation and/or various pharmaceutical additives.
  • the pediatric pharmaceutical compositions are preferably administered to patients under 12 or 15 years old.
  • the pediatric pharmaceutical compositions can be administered to patients who are under 27 days old after the birth, 28 days to 23 months old after the birth, 2 to 11 years old, 12 to 16 years old, or 18 years old.
  • the geriatric pharmaceutical compositions are preferably administered to patients who are 65 years old or over.
  • a usual oral dosage is 0.05 to 100 and preferably 0.1 to 10 mg/kg/day.
  • a usual dosage is 0.005 to 10 and preferably 0.01 to 1 mg/kg/day. The dosage may be administered in one to several divisions per day.
  • a compound of the present invention and a concomitant drug are administered is not restricted, and they can be administered to a subject of administration simultaneously or at intervals. Further, a compound of the present invention and a concomitant drug can be administered as two kinds of formulations comprising each active ingredient and as a single formulation comprising both active ingredients.
  • the dose of a concomitant drug can be suitably selected on the basis of a dosage which is clinically used.
  • the mixing ratio of a compound of the present invention and a concomitant drug can be suitably selected depending on a subject of administration, an administration route, a target disease, symptoms, combination and the like.
  • a subject of administration is a human, for example, 0.01 to 100 parts by weight of a concomitant drug can be used per part by weight of a compound of the present invention.
  • UV detection wavelength 254 nm
  • UV detection wavelength 254 nm
  • UV detection wavelength 254 nm
  • PPTS Pyridinium p-toluenesulfonate
  • Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)
  • DIAD Diisopropyl azodicarboxylate
  • DIBAL-H Diisobutylaluminium hydride
  • Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0)
  • Compound (I-1-4) was synthesized from Compound 15, in a similar way that Compound (I-1-2) was synthesized from Compound 10.
  • Compound 16 was synthesized by the method described in the following paper. Heterocycles, 2003, vol. 59, #2 p. 793-804
  • a solution of Compound 24 (58.4 mg, 0.090 mmol) in toluene (6 mL) was prepared and divided into two.
  • To one toluene solution were added Compound 9 (61.1 mg, 0.170 mmol), PdCl 2 (dtbpf) (5.9 mg, 9.1 ⁇ mol) and a 2 mol/L aqueous solution of potassium carbonate (45 ⁇ L, 0.090 mmol), and the mixture was stirred under microwave irradiation at 130° C. for 13 minutes. However, the reaction mixture was unreacted, thus toluene was removed under reduced pressure, and 1,4-dioxane (3 mL) was added thereto, then the mixture was again stirred at 130° C.
  • Compound 29 was synthesized from Compound 28, in a similar way that Compound 22 was synthesized from Compound 21.
  • Compound 30 was synthesized from Compound 29, in a similar way that Compound 23 was synthesized from Compound 22.
  • Compound 31 was synthesized from Compounds 30 and 1, in a similar way that Compound 24 was synthesized from Compounds 23 and 1.
  • Compound 36 was synthesized from Compound 35, in a similar way that Compound 23 was synthesized from Compound 22.
  • Compound 37 was synthesized from Compounds 36 and 1, in a similar way that Compound 24 was synthesized from Compounds 23 and 1.
  • Compound 38 was synthesized from Compounds 37 and 9, in a similar way that Compound 32 was synthesized from Compounds 31 and 9.
  • Compound 39 was synthesized from Compound 38, in a similar way that Compound 26 was synthesized from Compound 25.
  • Compound (I-1-7) was synthesized from Compound 39, in a similar way that Compound (I-1-5) was synthesized from Compound 26.
  • Compound 41 was synthesized from Compounds 24 and 40, in a similar way that Compound 32 was synthesized from Compounds 31 and 9.
  • Compound 42 was synthesized from Compound 41, in a similar way that Compound 26 was synthesized from Compound 25.
  • Compound (I-1-8) was synthesized from Compound 42, in a similar way that Compound (I-1-5) was synthesized from Compound 26.
  • Compound 43 was synthesized from Compounds 37 and 40, in a similar way that Compound 32 was synthesized from Compounds 31 and 9.
  • Compound 44 was synthesized from Compound 43, in a similar way that Compound 26 was synthesized from Compound 25.
  • Compound (I-1-9) was synthesized from Compound 44, in a similar way that Compound (I-1-5) was synthesized from Compound 26.
  • Compound 46 was synthesized from Compound 45, in a similar way that Compound 22 was synthesized from Compound 21.
  • Compound 50 was synthesized from Compounds 49 and 9, in a similar way that Compound 32 was synthesized from Compounds 31 and 9.
  • Compound 51 was synthesized from Compound 45, in a similar way that Compound 34 was synthesized from Compound 21.
  • Compound 52 was synthesized from Compound 51, in a similar way that Compound 35 was synthesized from Compound 34.
  • Compound 53 was synthesized from Compound 52, in a similar way that Compound 47 was synthesized from Compound 46.
  • Compound 54 was synthesized from Compound 53, in a similar way that Compound 48 was synthesized from Compound 47.
  • Compound 55 was synthesized from Compounds 54 and 6, in a similar way that Compound 49 was synthesized from Compounds 48 and 6.
  • Compound 56 was synthesized from Compounds 55 and 9, in a similar way that Compound 50 was synthesized from Compounds 49 and 9.
  • Compound (I-1-11) was synthesized from Compound 56, in a similar way that Compound (I-1-10) was synthesized from Compound 50.
  • Compound (I-1-12) was synthesized from Compound 59, in a similar way that Compound (I-1-7) was synthesized from Compound 9.
  • Compound 64 was synthesized from Compound 63, in a similar way that Compound 62 was synthesized from Compound 61.
  • the reaction mixture was filtered with celite, and ethyl acetate and saturated aqueous sodium chloride were added to the obtained filtrate, then a liquid-liquid separation was performed.
  • the organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography and further crystallized by ethyl acetate-hexane to obtain Compound 71 (137 mg, 55.5%).
  • Compound 72 was synthesized from Compound 71, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-4) was synthesized from Compound 72, in a similar way that Compound (I-2-3) was synthesized from Compound 68.
  • Compound 74 was synthesized from Compound 73, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-5) was synthesized from Compound 74, in a similar way that Compound (I-2-3) was synthesized from Compound 68.
  • Compound 77 was synthesized from Compound 75, in a similar way that Compound 70 was synthesized from Compound 69.
  • Compound 79 was synthesized from Compound 78, in a similar way that Compound 72 was synthesized from Compound 71.
  • Compound 81 was synthesized from Compound 71, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-7) was synthesized from Compound 81, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 82 was synthesized from Compound 67, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-8) was synthesized from Compound 82, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 84 was synthesized from Compound 83, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound 85 was synthesized from Compound 84, in a similar way that Compound (I-2-6) was synthesized from Compound 80.
  • Compound (I-2-9) was synthesized from Compound 85, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 86 was synthesized from Compound 83, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-10) was synthesized from Compound 86, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 88 was synthesized from Compound 87, in a similar way that Compound 78 was synthesized from Compound 77.
  • Compound (I-2-11) was synthesized from Compound 90, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 91 was synthesized from Compound 73, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-12) was synthesized from Compound 91, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 92 was synthesized from Compound 78, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-13) was synthesized from Compound 92, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 96 was synthesized from Compound 95, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-14) was synthesized from Compound 96, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • Compound 99 was synthesized from Compound 98, in a similar way that Compound 68 was synthesized from Compound 67.
  • Compound (I-2-15) was synthesized from Compound 99, in a similar way that Compound (I-2-1) was synthesized from Compound 62.
  • a buffer solution consisting of a 50 mM HEPES-NaOH buffer solution (pH 7.0), 100 mM NaCl, 10 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate(V), 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM disodium ß-glycerophosphate and 2 mM dithiothreitol, a human AMPK ⁇ 1ß1 ⁇ 1 enzyme (manufactured by Carna Biosciences, Inc.) was added in an amount to give a conversion rate of approximately 10% by reaction for 2 hours, and a compound dissolved in DMSO was added thereto so as to have a 1% DMSO concentration. The resulting liquid was left to stand for 10 minutes.
  • a human AMPK ⁇ 1ß1 ⁇ 1 enzyme manufactured by Carna Biosciences, Inc
  • a substrate solution consisting of a 50 mM HEPES-NaOH buffer solution (pH 7.0), 100 mM NaCl, 10 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate(V), 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM disodium 6-glycerophosphate, 2 mM dithiothreitol, 0.4 mM ATP and 3 ⁇ M FL-Peptide 7 (manufactured by Caliper Life Sciences, Inc.) was added in equal amount (10 ⁇ l in total). The resulting liquid was allowed to react at 25° C. for 2 hours, then 10 ⁇ l of 20 mM EDTA was added thereto to stop the reaction.
  • HEPES-NaOH buffer solution pH 7.0
  • 100 mM NaCl 100 mM NaCl
  • the reaction mixture was applied to a measuring device, LabChip EZ Reader II manufactured by Caliper Life Science, Inc., for detecting fluorescence by using differences in mobility due to differences in charge.
  • the setting conditions for the device were pressure, ⁇ 1.5 PSI; upstream voltage, ⁇ 2250 V; downstream voltage, ⁇ 400 V; post sample buffer sip time, 40 seconds; final delay, 120 seconds; and peak order, Product First.
  • a conversion rate was calculated from the peak heights of the obtained substrate and product.
  • the conversion rate when not containing a compound was used as a control, and a concentration dependent curve was made by plotting the rate of increase in activity to the control at each concentration of a compound.
  • the compound concentration showing 150% relative to the control (100%) was used as the EC 150 value, and the maximum rate of increase in activity within the measurement range was used as Emax.
  • the full length cDNAs of human AMPK ß2 (NM_005399.3) and human AMPK ⁇ 2 (NM_006252.3) were inserted into the MCS1 and MCS2 of the pETDuet-1 vector to prepare a human AMPK ß2 and human AMPK ⁇ 2 (6 ⁇ His tag at the 5′ terminus) expressing plasmid.
  • the plasmid was cotransfected with an expression plasmid, in which the full length cDNA of human AMPK ⁇ 1 (NM_002733.3) had been inserted into pET28b(+), into BL21 CodonPlus (DE3)-RIL to obtain an expression strain.
  • the expression strain was cultured in TB medium, followed by induction with 0.5 mM IPTG, and cultured at 25° C. for 3 hours and then harvested. After ultrasonication, supernatant was collected and applied to Histrap FF column (GE) and RESOUECE Q column (GE) to prepare 12.5 mg of purified sample containing three types of subunit from 1.8 L of broth.
  • Human AMPK ⁇ 2ß2 ⁇ 1 prepared in Escherichia coli was not phosphorylated and did not exhibit activity. Thus, phosphorylation treatment was carried out as pretreatment.
  • Human AMPK ⁇ 2ß2 ⁇ 1 in an amount to give a conversion rate of approximately 10% by reaction for 2 hours, and CaMKK2 in an amount capable of sufficiently imparting activity to AMPK for one hour were mixed in a buffer solution consisting of a 50 mM HEPES-NaOH buffer solution (pH 7.0), 100 mM NaCl, 5 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate(V), 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM disodium ß-glycerophosphate, 1 mM dithiothreitol and 0.2 mM ATP, and the resulting liquid was left to stand at 25° C. for 1 to 1.5 hours to sufficiently phosphorylate AMPK.
  • a buffer solution consisting of a 50 mM HEPES-NaOH buffer solution (p
  • a substrate solution consisting of a 50 mM HEPES-NaOH buffer solution (pH 7.0), 100 mM NaCl, 10 mM magnesium chloride, 0.1% bovine serum albumin, 0.2 mM sodium orthovanadate(V), 1 mM ethylene glycol-bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), 5 mM disodium ß-glycerophosphate, 2 mM dithiothreitol, 0.4 mM ATP and 3 ⁇ M FL-Peptide 7 (manufactured by Caliper Life Sciences, Inc.) was added in equal amount (10 ⁇ l in total). The resulting liquid was allowed to react at 25° C. for 2 hours, and 10 ⁇ l of 20 mM EDTA was added thereto to stop the reaction.
  • HEPES-NaOH buffer solution pH 7.0
  • 100 mM NaCl 100 mM NaCl
  • the reaction mixture was applied to a measuring device, LabChip EZ Reader II manufactured by Caliper Life Science, Inc., for detecting fluorescence by using differences in mobility due to differences in charge.
  • the setting conditions for the device were pressure, ⁇ 1.5 PSI; upstream voltage, ⁇ 2250 V; downstream voltage, ⁇ 400 V; post sample buffer sip time, 40 seconds; final delay, 120 seconds; and peak order, Product First.
  • a conversion rate was calculated from the peak heights of the obtained substrate and product.
  • the conversion rate when not containing a compound was used as a control, and a concentration dependent curve was made by plotting the rate of increase in activity to the control at each concentration of a compound.
  • the compound concentration showing 150% relative to the control (100%) was used as the EC 150 value, and the maximum rate of increase in activity within the measurement range was used as Emax.
  • Test Example 2 The results of Test Example 2 are shown below.
  • the compounds of the present invention have an excellent activating effect on an AMPK ⁇ 1 trimer and/or an AMPK ⁇ 2 trimer.
  • the CYP3A4 fluorescent MBI test is a test of evaluating Mechanism based inhibition (MBI) ability from enhancement by a metabolism reaction for CYP3A4 inhibition of the compound of the present invention. CYP3A4 inhibition was evaluated as an index 1-hydroxylation reaction of midazolam (MDZ) using pooled human hepatic microsomes.
  • MBI Mechanism based inhibition
  • NADPH was added to a remaining pre-reaction mixture to initiate a pre-reaction (with pre-reaction) and, after a predetermined time of a pre-reaction, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index.
  • the plate on which each index reaction had been performed was centrifuged at 3000 rpm for 15 minutes, and then midazolam 1-hydroxylation in the centrifuge supernatant was quantified by LC/MS/MS.
  • CYP1A2 7-ethoxyresorufin O-deethylation
  • CYP2C9 mephenytoin 4′-hydroxylation
  • CYP2D6 dextromethorphan O-demethylation
  • CYP3A4 terfenadine hydroxylation
  • reaction conditions were as follows: substrate, 0.5 ⁇ mol/L ethoxyresorufin (CYP1A2), 100 ⁇ mol/L tolbutamide (CYP2C9), 50 ⁇ mol/L S-mephenytoin (CYP2C19), 5 ⁇ mol/L dextromethorphan (CYP2D6), 1 ⁇ mol/L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test drug concentration, 1, 5, 10, 20 ⁇ mol/L (four points).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin (CYP1A2 metabolite) in the centrifuge supernatant was quantified by a fluorescent multilabel counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4′ hydroxide CYP2C19 metabolite
  • dextromethorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • Each 20 ⁇ L of freeze-stored Salmonella typhimurium (strains TA98 and TA100) is inoculated in 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and the cultures are preincubated at 37° C. under shaking for 10 hours.
  • 9 mL of TA98 culture is centrifuged (2000 ⁇ g, 10 minutes) to remove medium, and the bacteria is suspended in 9 mL of Micro F buffer (K 2 HPO 4 : 3.5 g/L, KH 2 PO 4 : 1 g/L, (NH 4 ) 2 SO 4 : 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgSO 4 .7H 2 O: 0.1 g/L), and the suspension is added to 110 mL of Exposure medium (Micro F buffer containing Biotin: 8 ⁇ g/mL, histidine: 0.2 ⁇ g/mL, glucose: 8 mg/mL).
  • Micro F buffer K 2 HPO 4 : 3.5 g/L, KH 2 PO 4 : 1 g/L, (NH 4 ) 2 SO 4 : 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgSO 4 .7H 2 O: 0.1 g/L
  • DMSO solution of the test substance (eight dose levels from maximum dose 50 mg/mL at 2-fold ratio); DMSO as negative control; 50 ⁇ g/mL of 4-nitroquinoline-1-oxide DMSO solution as positive control for strain TA98 without metabolic activation conditions; 0.25 ⁇ g/mL of 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution as positive control for strain TA100 without metabolic activation conditions; 40 ⁇ g/mL of 2-aminoanthracene DMSO solution as positive control for strain TA98 with metabolic activation conditions; or 20 ⁇ g/mL of 2-aminoanthracene
  • the solubility of a compound was determined under a condition in which 1% DMSO was added.
  • a 10 mM compound solution was prepared using DMSO, and then 6 ⁇ L of the compound solution was added to 594 ⁇ L of artificial intestinal juice in pH 6.8 (to 250 mL of a 0.2 mol/L potassium dihydrogen phosphate reagent solution were added 118 mL of a 0.2 mol/L NaOH reagent solution and water to provide a final volume of 1000 mL).
  • the mixed solution was filtrated with suction.
  • the filtrate was diluted twice with methanol/water (1/1), and then a concentration in the filtration was measured with HPLC or LC/MS/MS by the absolute calibration method.
  • a reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human hepatic microsomes.
  • a buffer 50 mmol/L Tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride
  • test compound in the centrifuge supernatant was quantified by LC/MS/MS, and a remaining amount of the test compound after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.
  • Hydrolysis reaction was performed in the absence of NADPH and glucuronidation reaction was performed in the presence of 5 mM UDP-glucuronic acid in place of NADPH, followed by similar operations.
  • test substances are put into appropriate containers.
  • 200 ⁇ L of JP-1 fluid sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to reach 1000 mL
  • 200 ⁇ L of JP-2 fluid phosphate buffer (pH 6.8) 500 mL and water 500 mL
  • 200 ⁇ L of 20 mmol/L TCA (sodium taurocholate)/JP-2 fluid TCA 1.08 g and water to reach 100 mL.
  • TCA sodium taurocholate
  • the mixtures are filtered, and 100 ⁇ L of methanol is added to each of the filtrate (100 ⁇ L) so that the filtrates are two-fold diluted.
  • the dilution ratio is changed if necessary.
  • the containers are sealed and shaken. Quantification is performed by HPLC with an absolute calibration method.
  • test substance was forcibly administered to the stomach by using a gavage tube.
  • test substance was administered via tail vein using a syringe with a needle.
  • AUC area under the plasma concentration-time curve
  • the compound of the present invention lactose and calcium stearate are mixed.
  • the mixture is crushed, granulated and dried to give a suitable size of granules.
  • calcium stearate is added to the granules, and the mixture is compressed and molded to give tablets.
  • the compound of the present invention lactose and calcium stearate are mixed uniformly to obtain powder medicines in the form of powder or fine granules.
  • the powder medicines are filled into capsule containers to give capsules.
  • the compound of the present invention, lactose and calcium stearate are mixed uniformly, and the mixture is compressed and molded. Then, it is crushed, granulated and sieved to give a suitable size of granules.
  • the compound of the present invention and crystalline cellulose are mixed and granulated, then tableted to give orally disintegrating tablets.
  • the compound of the present invention and lactose are mixed, crushed, granulated and sieved to give a suitable size of dry syrups.
  • the compound of the present invention and phosphate buffer are mixed to give injections.
  • the compound of the present invention and phosphate buffer are mixed to give injections.
  • the compound of the present invention and lactose are mixed and crushed finely to give inhalations.
  • the compound of the present invention and petrolatum are mixed to give ointments.
  • the compound of the present invention and base such as adhesive plaster or the like are mixed to give patches.
  • the compounds of the present invention show an AMPK activating effect. Therefore, the compounds of the present invention are very useful as a therapeutic agent for type I diabetes, type II diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia and hypertension.

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EP3421467A4 (fr) 2016-02-26 2019-08-07 Shionogi & Co., Ltd Dérivé 5-phénylazaindole possédant un effet d'activation de l'ampk
US20190135834A1 (en) * 2016-04-26 2019-05-09 Shionogi & Co., Ltd. 5-substituted azabenzimidazole derivative having ???? activation action
CN115996917A (zh) 2020-05-06 2023-04-21 艾捷斯治疗公司 作为jak2抑制剂的6-杂芳基氧基苯并咪唑和氮杂苯并咪唑
CN116323608A (zh) 2020-05-19 2023-06-23 卡尔优普公司 Ampk活化剂
AU2021297323A1 (en) 2020-06-26 2023-02-16 Kallyope, Inc. AMPK activators
AU2022388555A1 (en) 2021-11-09 2024-05-02 Ajax Therapeutics, Inc. 6-he tero aryloxy benzimidazoles and azabenzimidazoles as jak2 inhibitors
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